Summary/Abstract Malaria remains one of the most important global health challenges, with an estimated 216 million cases and 445,000 deaths each year. Malaria disproportionately affects sub-Saharan Africa, where 90% of cases and deaths occur. Over the last 15 years there has been a dramatic increase in the use of proven control interventions including long-lasting insecticidal bednets (LLINs), indoor residual spraying of insecticide (IRS), and treatment of malaria with artemisinin-based combination therapies (ACTs). These interventions have resulted in a marked reduction in the burden of malaria across Africa. However, progress has not been uniform, and in fact slowest in countries with the highest burden, such as Uganda. Our ?PRISM? program based in Uganda represents the East African region for the International Centers of Excellence for Malaria Research (ICEMR) network. Uganda is emblematic of the challenges faced by high burden countries, where routine surveillance systems are inadequate to assess trends in the burden of malaria or to monitor the impact of control interventions. Through PRISM we have implemented a comprehensive malaria surveillance program including enhanced health facility-based surveillance and detailed longitudinal studies in regions with differing transmission intensities. Complementary laboratory-based studies include surveillance for markers of antimalarial drug and insecticide resistance and serologic measures of malaria exposure. These studies have greatly improved our understanding of the epidemiology of malaria in Uganda and the impact of control interventions. We have learned that the burden of malaria remains high following universal LLIN distribution, likely due to the spread of pyrethroid resistance. IRS has been more effective, but limited in its scope due to high cost, with resurgence in areas where it has been withdrawn. ACTs remain highly efficacious in Uganda, but use has been limited to treatment of symptomatic disease; drugs are not utilized to prevent malaria in children, despite a huge burden of disease. We have also shown that asymptomatic parasitemia is common, even in areas with low incidence of disease, and that school-aged children represent an important reservoir for transmission. In this revision application, our overall objective will be to extend the aims of our PRISM program to evaluate novel approaches towards the prevention of malaria. We thus propose: 1) an observational study to collect background data to inform the design of a future study of intermittent preventive treatment of malaria in schoolchildren as a means of reducing community level transmission intensity; and 2) an intervention study to compare traditional and new generation LLINs using a cluster-randomized trial design. These studies will take advantage of our established infrastructure to help Uganda and other African countries identify optimal interventions for further reducing the burden of malaria and clearing a path towards elimination of the disease.